Genus-wide analysis of Fusarium polyketide synthases reveals broad chemical potential

Authors: Brown, Daren; Kim, Hye-Seon; McGovern, Amy; Probyn, Crystal; Proctor, Robert

Submitted to: Fungal Genetics and Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/18/2022
Publication Date: 4/22/2022
Citation: Brown, D.W., Kim, H.-S., McGovern, A.E., Probyn, C.E., Proctor, R.H. 2022. Genus-wide analysis of Fusarium polyketide synthases reveals broad chemical potential. Fungal Genetics and Biology. 160. Article 103696. https://doi.org/10.1016/j.fgb.2022.103696.
DOI: https://doi.org/10.1016/j.fgb.2022.103696

Interpretive Summary: Species of the fungus Fusarium pose a dual threat to agriculture by causing destructive crop diseases and producing toxins that pose health hazards to humans, pets, and livestock. Some of the toxins are derived polyketides, a large class of metabolites that are synthesized by enzymes known as polyketide synthases (PKSs). To better understand the diversity of polyketide-derived toxins produced by Fusarium, we examined the PKS-encoding genes that are present in genome sequences of 206 species of the fungus. We identified 2974 PKS genes that could be resolved into 122 distinct groups based on similarities and differences in DNA sequences. Based on our understanding of how PKSs function, we estimated that the 122 groups of PKS genes confer the ability to produce 112 structurally distinct polyketides, including polyketides from which toxins are derived. We also found evidence that several of the PKS genes are involved in production of medicines, including the antibiotic chaetoviridin, the cholesterol medication lovastatin, and the immune-suppressing drug cyclosporine. These results provide critical information on the variety of polyketide-derived metabolites produced by diverse species of Fusarium, which in turn contributes to the understanding of the hazard the species pose to food and feed safety.

Technical Abstract: The genus Fusarium includes pathogens of global concern to animal and plant health. Natural products (NPs) synthesized by Fusarium can contribute to pathogenesis or competitiveness of the fungus in the environment and to disease in animals including cancer and neural tube defects. Polyketide synthases (PKSs) are a family of large, multi-domain enzymes that are required for synthesis of most fungal NPs. To gain insight into the NP potential of Fusarium, we retrieved 2974 PKS gene sequences from the genomes of 206 Fusarium species. Phylogenetic analysis resolved these PKSs, along with 118 previously described PKSs from other fungi, into 122 clades. Based on results from previous studies, we propose that PKSs in the same clade generally synthesize the same polyketide, which is structurally distinct from polyketides synthesized by PKSs in other clades. We predict that the 122 clades potentially produce 112 structurally distinct families of polyketide-derived NPs because some NPs (e.g., zearalenone) require two PKSs for their synthesis. Collectively, the clades include PKSs required for synthesis of six NPs whose production has not previously been reported in Fusarium, including two NPs with significant pharmaceutical interest: chaetoviridin and lovastatin. Our results highlight the NP diversity of Fusarium and the potential of the genus to produce metabolites with medical and other applications.